Implantable
Cardioverter-Defibrillators (ICDs) carry a class I indication for implantation
to prevent sudden cardiac death (SCD) in patients with symptomatic Heart Failure
who have a Left Ventricular Ejection Fraction (LVEF) less than 35% despite
optimal medical therapy[1]. However there has been a long held
suspicion among the heart failure and arrhythmia communities that the efficacy
of primary prevention ICDs in heart failure of non-ischaemic aetiology is lower
than that of ischaemic aetiology. This is borne out in disparity of level of
evidence supporting the recommendations: B for non-ischaemic aetiology compared
to A for ischaemic cardiomyopathy[1].

The DANISH
trial, published in September 2016 in the New England Journal of Medicine, has
ignited the debate with its finding that prophylactic
ICDs in non-ischaemic cardiomyopathy do not result in reduced mortality in
a large randomized controlled trial (RCT)[2]. Recruitment took place between
2008 and 2014 at five centres and 1,116 patients were randomized to ICD or
medical therapy in a 1:1 fashion. Median age was 64 (56-72) in the ICD group
and mean LVEF was 25% (IQR 20-30). Over 90% of patients were on beta-blockers
and ACE-inhibitors, whilst just under 60% were taking mineralocorticoid
antagonists (MRA). 58% of patients also received a left ventricular lead as
part of Cardiac Resynchronization Therapy (CRT).[2]

Median
follow up was 5.5 years and the primary outcome was all-cause mortality, which
was not significantly different between ICD and medical therapy (HR 0.87,
confidence interval (CI) 0.68-1.12, p=0.28). When considering secondary
outcomes, there was also no significant difference in cardiovascular death (HR
0.77, CI 0.57-1.05, p=0.10) but ICDs were associated with a significant reduction
in Sudden Cardiac Death (HR 0.5, CI 0.31-0.82, p=0.005). Of note the total
event rate for the primary outcome was 22.4% (rate of all-cause mortality in
all patients), which is an annualized rate of around 4% per year, which is
lower than older RCTs in the same population.[2]

Previous RCTs in the non-Ischaemic population

The
controversy regarding the efficacy of prophylactic ICDs to reduce mortality in non-ischaemic
cardiomyopathy may originate from the lack of individual trials showing benefit
of ICDs. Of the 5 primary prevention RCTs (CAT 2002[3], AMIOVERT 2004[4], DEFINITE 2004[5], COMPANION 2004[6], SCD-HeFT 2005[7]) that included patients with
non-ischaemic cardiomyopathy only COMPANION showed a significant reduction in
all-cause mortality for non-ischaemic patients. This analysis was not included
in the original analysis but has been determined from the kaplan-meier curves
in the original publication by Shun-Shin et al in recent meta-analysis[8]. SCD-HeFT showed a trend towards
benefit for all-cause mortality but did show a reduction in SCD.

When these
trials (excluding COMPANION, whose non-ischaemic population had not yet been
analysed) were meta-analysed by Desai et al[9] there does appear to be a clear
reduction in all-cause mortality (HR 0.69, CI 0.55-0.87, P = 0.002). This forms
the basis for the recommendation for implantation in the non-ischaemic
population in international guidelines. It was felt that the lower event rate
in the non-ischaemic population may have resulted in these trials being
underpowered individually but collectively show the benefit of ICDs.

Meta-analysis including DANISH

Shun-shin
et al have meta-analysed the aforementioned non-ischaemic primary prevention
ICD trials along with DANISH and their analysis of the data from COMPANION. They
find that when the negative finding of DANISH is combined with the 5 previous
trials, the benefit of ICD over medical therapy persists (HR 0.76, CI
0.64-0.90, p=0.001). There was a low level of I2 heterogeneity with
this result. This indicates that the DANISH finding falls within the expected
result from previous data.[8]

Should DANISH change practice?

The
inevitable question is whether or not the negative result from DANISH should
change implantation practice for patients with non-ischaemic cardiomyopathy.
The DANISH authors, along with an accompanying editorial by McMurray, argue
that the improvement in medical therapy for heart failure has reduced the risk
of death over time. There is a massive difference in the rates of beta
blockade, ACE-I and MRA prescription rates across the trials (4% of CAT, 2002,
patients were on beta blockers compared to 92% in DANISH, 2016) and newer
pharmacological agents such as Neprilysin inhibitors (Entresto) may further
reduce event rates in the future.

However, it
should be considered that, even prior to DANISH, it has been understood that
individually underpowered trials need to be combined to understand the true
benefit of an intervention in question and this was the case for non-ischaemic
cardiomyopathy. The addition of DANISH to the data set does not, on the face of
it, change the summary meta-analysed result that ICDs benefit.

There are a
few other considerations that may influence decision making. MADIT-RIT[10], along with other similar trials,
have demonstrated that longer detection times and higher thresholds for
delivering ICD therapy (shocks and ATP, anti-tachycardia pacing) reduce
mortality when compared to traditional programming. These programming settings
are now widely applied and are thus improving the efficacy of ICDs. The
supplementary appendices of DANISH indicate that programming during the trial
did changed as these trials were published during recruitment for DANISH,
however it is not clear what proportion of patients in DANISH had MADIT-RIT
style programming in place and for how long.

Regarding
cost-effectiveness, an economic evaluation of DANISH as an individual trial may
increase the cost per QALY of implantation to a value above accepted
willingness-to-pay thresholds but using the meta-analysed efficacy, the
cost-effectiveness is likely to remain similar – so the question rests, again,
on whether we accept DANISH as an individual trial with modern medical therapy
or view it in the context of previous similar trials.

Furthermore,
there is ongoing work into new ways to improve the ICD efficacy/safety profile
and novel predictors of ventricular arrhythmia in heart failure that may result
in better patient selection. So just as medical therapy is acquiring new agents
into its pantheon, ICD therapy is also improving, so an inexorable march to
lower event rates through improved medical therapy eliminating the benefit of
ICD therapy should not be assumed.

References

1. Priori,
S.G., et al., 2015 ESC Guidelines for the
management of patients with ventricular arrhythmias and the prevention of
sudden cardiac death: The Task Force for the Management of Patients with
Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the
European Society of Cardiology (ESC). Endorsed by: Association for European
Paediatric and Congenital Cardiology (AEPC). Eur Heart J, 2015. 36(41): p. 2793-867.